Steroidal c-6 alkinyl or alkenyl derivatives and process for the preparation thereof



United States Patent 3,083,946 STEROIDAL C-6 ALKINYL OR ALKENYL DERIVA- TIVES AND PROCESS FOR THE PREPARATION THEREOF John A. Zderic and Howard J. Ringold, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Jan. 19, 1960, Ser. No. 3,277 Claims priority, application Mexico Jan. 20, 1959 33 Claims. (Cl. 260-43955) R. l R. R-- l R" Q E In the above formulae, R represents hydrogen or lower alkyl containing 1 to carbon atoms; R represents hydrogen or methyl; A represents fl-hydroxy, fl-acyloxy, 17alower alkyl-fifi-hydroxy, 17a-lower alltin(1)yl-17,6-hydroxy,l7a-lower alken(l)yl-17B-hydroxy; Y represents u-hydroxy, ,B-hydroxy, keto or hydrogen. E represents fl-lower alkinyl and B-lower alkenyl groups containing 1 to 8 carbon atoms and may be of straight, branched, cyclic or mixed straight or branched cyclic and may also be substituted by hydroxy, alkoxy or halogen as chlorine, bromine and fluorine. R represents fl-hy-droxy, keto or cyclic alkylene dioxy. The aforesaid acyl groups are derived from a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, saturated or unsaturated, straight chain or branched chain aliphatic, cyclic, cycliceliphatic, aromatic and may be substituted by, for example, halogen. Typical ester groups are the formate, acetate, propionate, butyrate, hemisuccinate, enanthate, caproate,

"ice

benzoate, trimethylacetate, phenoxyacetate, phenylpropionatc, cyclopentylpropionate, trifluoroacetate and fl-chloropropionate. When A is 1741-10WBI' alkin(l)yl-17fi-hydroxy in a A -3-ketone, the compounds exhibit progestational activity.

The novel compounds of this invention which are also progestational type agents having anti-estrogenic, antiandrogenic and anti-pituitary activity may be characterized by the following formulae:

In the above formulae R, R Y and E represent the same groups as heretofore set forth; R represents hydrogen, hydroxy or ocyloxy, the acyl being derived from a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms as described hereinabove. X represents hydrogen, chlorine, bromine or fluorine and when Y is hydrogen, X must be hydrogen.

Similarly the novel C-6 substituted derivatives of the diesters of hydrocarbon carboxylic acids of the same type as above stated of Reichsteins Compound S exhibit the same biological activity, in addition to being useful intermediates for the preparation of cortical hormones by introducing an oxygen function at 0-11 by known means.

The novel compounds of the present invention which exhibit anti-inflammatory, thymolytic and glycogenic activity may be illustrated by the following formulae:

ClIrOR '---0 RT i TR In the above formulae, R, R and E have the same meaning as hereinabove set forth. R represents hydrogen or acyl; Y represents keto, a-hydroxy or fl-hydroxy. X represents hydrogen, chlorine, bromine or fluorine. R represents hydrogen, u-methyl or fi-methyl. When R represents hydrogen, R' represents hydrogen; when R represents acyl, R represents hydrogen or acyl. The acyl group in each instance is derived from a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms of the character as heretofore stated.

Certain novel compounds of the present invention are also valuable intermediates for the preparation of 6;?- (dihydroxy lower alkylene) derivatives of androstane and pregnane compounds which may be prepared by hydroxylation of the fifi-lower alkenyl, particularly the tSfi-vinyl compounds of the present invention with osmium tetroxide.

The preparation of the C6 substituted cyclopentanopolyhydrophenanthrene compounds which form the subject of the present invention may be illustrated by the following equation, insofar as rings A and B are concerned. When a A -3-keto compound is used as the starting material; the process proceeds in the following manner:

l Ketallzatlon and O O: epoxidatlon lalkinyl Mg B r reduction "Q 0 n o 0 n 6 (J H=G H R" l hydrolysis H=OH It ldchydration C OR Catalytic hydrogenation h 0 6,8-vinyl-5a-hydroxy compound either by catalytic When starting with a 3fl-hydroxy compound, the process proceeds in a similar manner, as follows:

In the above equations, R represents hydrogen or lower alkyl.

In practicing the processes above outlined, a 511,60;- oxido compound of the androstane or pregnane series, substituted at C-3 by hydroXy or 3-cyclic alkylene dioxy, preferably 3-ethylenedioxy, is reacted with an alkinyl Grignard reagent, preferably acetylenic magnesium halide and more particularly ethinyl magnesium bromide under reflux conditions in a solvent such as tetrahydrofurane to form a 6fl-ethinyl-5a-hydroxy compound, The latter can then be converted to the 3-keto 6fi-ethinyl ia-hydroxy compound by hydrolysis of the 3-ketal group with an acid such as dilute perchloric acid in tctrahydrofurane, ptoluenesulfonic acid in aqueous acetone, or hydrochloric or sulfuric acid in aqueous lower alkanols, or by oxidation of the SB-hydroxy group by treatment with an oxidizing agent as for example, chromic acid. The GB-ethinyl- Sa-hydroxy compound substituted at C-3 by keto, B-hydroxy or ethylenedioxy is reduced to the corresponding hydrogenation in the presence of a hydrogenation catalyst such as palladium on calcium carbonate in a solvent such as pyridine or by the use of lithium in liquid ammonia in the absence of alcohol. Where a 6,8,l7a-di-ethinyl compound is hydrogenated, reduction of the l7a-ethinyl group to l7a-vinyl is effected at the same time.

Prior to the reduction step, the 3-keto-6fi-ethinyl-5a-hydroxy compounds may be dehydrated as by treatment with potassium acetate and methyl alcohol under reflux conditions or with thionyl chloride in pyridine solution at low temperature, to yield the corresponding 6t9-ethinyl-A -3- keto compound, which may then subsequently be reduced to the 6fi-vinyl-A -3-keto derivative. It is also within the scope of the present invention to effect dehydration subsequent to the reduction step.

The alkenyl moiety may also be introduced directly at C-6 by the use of an alkenyl magnesium halide in an inert solvent such as dioxane under reflux conditions, or lower temperatures for a long period of time.

Alternatively the 6fi-ethinyl-A -3-keto compound may be treated with hydrochloric acid which results in the addition of the elements of hydrogen and halogen to the acetylenic bond with simultaneous inversion of the steric configuration at C-6 to form the fiu-[l-Ci'liOl"O'Vinyi)-A '3 keto compound.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I A stream of acetylene was introduced into a cooled mixture of 250 cc. of 4 N methylmagnesium bromide in ether and 1000 cc. of tetrahydrofurane, for 3 hours and taking care that the temperature did not rise over C.

There were then added 10 g. of 3-ethylenedioxy-5a,6aoxido-androstan-flfi-ol dissolved in 100 cc. of tetrahydrofurane and the mixture was refluxed for hours under an atmosphere of nitrogen. It was then cooled, poured into 5 l. of ice cold aqueous 20% ammonium chloride solution; the product was extracted with several portions of ethyl acetate, the combined extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Chromatography of the residue on neutral alumina afforded the pure GB-ethinyl-S-ethylenedioxy-androstane-5a,17p-diol, M.P. l08110 C., [0:] 47 (pyridine).

A solution of 5 g. of the above compound in 100 cc. of acetone was treated with 500 mg. of p-tolucnesulfonic acid and kept for 4 hours at room temperature. It was then diluted with water and the precipitate formed was collected by filtration, washed with water, dried, chromatographed on neutral alumina and finally recrystallized from acetone. There was thus obtained 6fi-ethinylandrostane- 5a,l7 3-diol-3-one with M.P. 240-245", raised to 258- 260 C. after several recrystallizations, [411D l9 (chloroform).

A solution of 1 g. of the above compound in 15 cc. of pyridine was cooled to 0 C. and treated with 1 cc. of thionyl chloride for 8 minutes while cooling in an ice bath. The mixture was poured into cc. of water, the product was extracted with several portions of ethyl acetate and the combined extract was washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. The residue was dissolved in acetone, decolorized with charcoal and then purified by repeated recrystallization from acetone, thus affording Gfl-ethinyl-testosterone.

A suspension of 900 mg. of 2% palladium on calcium carbonate in 150 cc. of pure pyridine was treated with hydrogen at room temperature for 3 hours to pre-reduce the catalyst. There was then added 3 g. of GB-ethinyltestosterone and the mixture was hydrogenated under continuous stirring at room temperature until the absorption of hydrogen practically ceased, which occurred when 1 molar equivalent of hydrogen had been absorbed. The catalyst was removed by filtration washing the filter with a little pyridine and the combined filtrate and washings was evaporated to dryness under reduced pressure. The residue was dissolved in ether, the ether solution was consecutively washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and finally again with water, dried over anhydrous sodium sulfate and the ether was evaporated. Recrystallization of the residue from acetone-hexane yielded fifi-vinyl-testosterone.

The starting material, namely 3-ethylenedioxy-5a,6aoxido-androstan-UB-ol was obtained by the following method of preparation:

A mixture of 5 g. of testosterone, 300 cc. of anhydrous benzene, 35 cc. of ethyleneglycol and 500 mg. of p-toluenesulfonic acid monohydrate was refluxed for 24 hours, with the use of a water separator for removing the water formed during the reaction; the cooled mixture was treated wlth cc. of 5% aqueous sodium carbonate solution and 200 cc. of water and the benzene layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and the benzene was evaporated. By chromatography on neutral alumina there was obtained 3-ethylenedioxy-M-androsten-l75-01.

To a cooled solution of 5 g. of the above compound in 100 cc. of chloroform was added an ether solution of monoperphthalic acid containing 1.2 molar equivalents of the reagent; the mixture was kept for 12 hours in the dark at room temperature and then diluted with water. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Chromatography of the residue on neutral alumina yielded 3-ethylenedioxy-5a,6a-oxido-androstan-17fi-ol.

Example 2 By following the procedure described in Example 1, 5 g. of 17DL-lTlBthYl-3-BthyiEI1dlOXy-5OL,60t-OXidO-3l'ldl05t3fl- 175-01. obtained from 17u-methyl-testosterone by applying the preparation method of Example 1, yielded successively 6,8-ethinyl-17a-methyl-3-ethylenedioxy-androstane- 5a,l7B-diol and 6B-ethinyl-l'Ia-methyl-androstane-Sa,17,3- diol-3-one.

A solution of l g. of the above compound in 30 cc. of methanol was treated with l g. of potassium acetate and the mixture was refluxed for 1 hour. It was then cooled, poured into ice water and the formed precipitate collected. Crystallization from methylene chloride-ether gave the pure fi-ethinyl-l7a-methyl-testosterone.

The later compound was hydrogenated in pyridine solution and the using 2% palladium on calcium carbonate as catalyst, in accordance with the hydrogenation method of Example 1, thus affording 613-vinyl-17a-methyl-testosterone.

Example 3 By following the procedure described in Example 1, 5 g. of l7a-ethinyl-3-ethylenedioxy-5a,6a-oxido-androstan-17bol, obtained from 17a-ethinyl-testoster0ne by applying the preparation method of Example 1, was converted successively into 6,9,l7a-bis-ethinyl-3-ethylenedioxy-androstane- 511,173 diol; 6B,l7a-bis-ethinyl-androstane-Sa,17,8-diol-3- one and 65,l7a-bis-ethinyl-testosterone.

A solution of 1 g. of the latter compound in 20 cc. of pyridine was added to a suspension of 500 mg. of 2% palladium on calcium carbonate in cc. of pyridine, that have been previously reduced. The mixture was hydrogenated under continuous stirring at room temperature until 2 molar equivalents of hydrogen were absorbed. The catalyst was removed by filtration and the solution was worked up in accordance with the method described in Exampie 1. There was thus obtained 6p,l7a-di-vinyltestosterone.

Example 4 By following the procedure described in Example 1, but substituting the ethinylmagnesium bromide for vinylrnagnesiurn bromide, l7wethinyl-3-ethylenedioxy-5a,6aoxido-androstan-flfl-ol was converted successively into 6,8-vinyl-l7a-ethinyl-3-ethylenedioxy androstane-5a,l7fldiol; op-vinyl-lla-ethinyl androstane-Sa, 17 p-diol-B-one and 6,8-vinyl-1Methinyl-testosterone.

Example 5 5 g. of 3-ethylenedioxy-5a,6a-oxido-9-nor-androstan- -01, obtained from l9-nor-ethinyl-testosterone, by the preparation method described in Example 1, was processed in accordance with the method described also in Example 1, but substituting the stream of acetylene for butine-l, there were thus successively obtained tifi-butin l )yl-3-ethylenedioxy-l9-norandrostane-5ot,l7B-diol; 6ebutin(1)yl-l9-nor-androstane-5a,l7fi-diol-3-one and 6 8- butin( l )yll Q-nQr-testosterone.

Example 6 A solution of 5 g. of 3-ethylenedioxy-5a,6a-oxidoandrostan-l7,6-o1-ll-one, obtained from ll-keto-testosterone by the preparation method described in Example 1, in 100 cc. of tetrahydrofurane was treated with ethinylmagnesium bromide, in accordance with the method described in Example 1, and the resulting 6fi-ethinyl-3-ethylenedioxy-androstane-Sa,l7fi-diol-ll-one was hydrolized with p-toluenesulfonic acid in acetone solution, thus yielding 6p-ethinyl-androstan-5a,17B-diol-ll-one.

A mixture of 1 g. of the above compound, 5 cc. of pyridine and 3 cc. of acetic anhydride was kept at room temperature for 4 hours, it was poured into water, the formed precipitate was filtered, washed with water and dried, thus producing the 17-acetate of GB-ethinyl-androstan-5u,17/3-diol-1l-one.

The above crude compound was treated with thionyl chloride in pyridine solution, by following the dehydration method of Example 1, to produce the acetate of 6;.3-ethinyl-1l-keto-testosterone.

Hydrogenation of the latter compound in pyridine solution, and using 2% palladium on calcium carbonate as catalyst, in accordance with the method of Example 1, gave the acetate of 6 8-vinyl-1l-keto-testosterone.

Example 7 A solution of 5 g. of 2a,17a-dlmethy1-5a,6a-0Xld0- androstan-17,B-ol, obtained from 20:,l7ot-Cll1IlCIhYl-1CSIOS- terone by ketalization followed by epoxidation, in accordance with the preparation method of Example 1, was treated with ethinylmagnesium bromide, and the resulting 2m,17a-dimethyl-65-ethinyl 3 ethylenedioxy-androstane, 5a,17;3-diol was hydrolyzed with p-toluenesulfonic acid in acetone solution, in accordance with the method described in Example 1 to produce 20:,17wdlt116thYl-613-8thinyl-androstane-Sa,17fl-diol-3-one.

The above compound was dehydrated with potassium acetate in methanol by following the procedure described in Example 2, thus giving 2a,17a-dimethyl-6B-ethinyltestosterone.

Example 8 In accordance with the hydrogenation method of Example 1, 2 g. of 2a,17a-dimethyl-6 3-ethinyl-androstane- 5a,17;S-diol-3-one, intermediate in the preceding example, was converted into 211,17rx-dimethyl-fifi-vinyl-androstane-5a,17B-diol-3-one.

Dehydration of the latter compound with potassium acetate in methanol, by applying the method described in Example 2, gave 2a,17a-dimethyl-ofi-vinyl-testosterone.

Example 9 10 g. of 5a,6a-oxido-17u-methyLandrostan-3B,l7u-diol- 3monoacetate, described by H. J. Ringold et al. in J.O.C., 22, 99 (1957) was treated with ethinylmagnesium bromide, in accordance with the method described in Example 1, to produce GB-ethinyl-17a-methyl-androstane- 3;3,5a,17a-triol.

A solution of 3 g. of the above compound in 120 cc. of acetone was cooled to C., flushed with nitrogen and treated with an 8 N solution of chromic acid, under stirring at 0 C. and under an atmosphere of nitrogen until the color of chromium trioxide persisted in the mixture (the 8 N solution of chromic acid had been prepared by dissolving 26.7 g. of chromium trioxide in 23 cc. of concentrated sulfuric acid and diluting with distilled water to 100 cc.). The mixture was stirred for minutes more at 0 C. under an atmosphere of nitrogen, then diluted with ice water and the precipitate was collected, washed with water, dried and recrystallized from acetone-ether, to produce fifl-ethinyl-l7lx-methyl-androstan-5a,l7j3-diol-3-one, identical with that obtained in Example 2. Dehydrogenation of the above compound with potassium acetate in methanol, as described in Example 2, gave 6,8-ethinyl-17or-methyl-testosterone.

Example In accordance with the method of Example 1, 2 g. of 5a,6a-oxido-androstane-3,8,l7fi-diol diacetate, described by Bowers et al. in Tetrahedron 1958, p. 14, was converted into 6fl-ethinyl-androstane-3 3,5a,17B-triol. Hydrogenation of the above compound in accordance with the method of Example 1, afforded fifi-vinyl-androstan- 3fl,5a,l7;9-triol.

Example 1'1 A solution of 5 g. of 3,ZO-bis-ethylenedioxy-Sa,6aoxido-pregnane obtained from progesterone by the preparation method of Example 1, was treated with ethinylmagnesium bromide in accordance with the method of Example 1, to afford 6fl-ethinyl-3,ZO-bis-ethylenedioxypregnan-Sa-OI, M.P. 144-146" C.; [111 35 (chloroform). The ketal groups were then hydrolized with p'toluenesulfonic acid in acetone, to afford 6fi-ethinylpregnan-5a-ol-3,20-dione, M.P. 288-290 C. (dec.); [M +51.4 (chloroform). Dehydration of the above compound with thionyl chloride in pyridine gave 65- ethinyl-progesterone, M.P. ISO-184 C.; [ab +46 (dioxane).

Hydrogenation of the latter compound in pyridine solution, using 2% palladium on calcium carbonate as catalyst, in accordance with the method of Example 1, gave 6fl-vinyl-progesterone.

Example 12 By following the procedure described in Example 1, but using 3,20-bis-ethy1enedioxy-5a,6a-oxido-pregnan-17a-ol as starting material, obtained from l7u-hydroxy-progesterone by the preparation method described in Example 1, there were obtained successively, 6fl-ethinyl-3,20-bisethylenedioxy-pregnan-Sa,l7a-diol, MAP. 210213 C.; [ab-48 (chloroform); SB-ethinyI-pregnan-Sa,17a-diol- 3,20-dione and 6,8-ethinyl-17a-ol-3,20-dione, i.e. GB-ethinyl-17a-hydroxy-progesterone.

A mixture of 1 g. of the above compound, 40 cc. of acetic acid, 20 cc. of acetic anhydride and 1 g. of ptoluenesulfonic acid was kept at room temperature for 1 hour. The resulting dark solution was poured into ice water and heated on the steam bath for 30 minutes. It was then extracted with ethyl acetate, and the organic extract washed with water, 5% sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue gave Gfi-ethinyl-l'la-acetoxy-progesterone.

Hydrogenation of the latter compound in accordance with the method described in Example 1, afforded 6,3 vinyl-17a-acetoxy-progesterone.

Example 13 To a solution of ethylmagnesium bromide, prepared from 3.63 g. of magnesium, 16.3 g. of ethyl bromide and 350 cc. of ether, was added 10.52 g. of ethoxyacetylene dissolved in 175 cc. of ether, under continuous stirring and in the course of 30' minutes. The mixture was stirred for 1 hour further and to the ether solution of ethoxyacetylene bromide thus obtained there was then added a solution of 5 g. of 3,20-bis-ethylenedioxy-5u,6aoxido-pregnane in cc. of benzene. The mixture was refluxed for 5 hours under an atmosphere of nitrogen, poured into 450 cc. of 20% aqueous ammonium chloride solution and the organic layer was separated, washed with water to neutral, dried over anhydrous sodium sulfate and the solvent was evaporated. By chromatography of the residue on neutral alumina there was obtained 6/i-ethoxyethinyl-3,20-bis-ethylenedioxy-pregnan- Soc-01, which was then treated with ptoluenesulfonic acid in acetone solution, in accordance with the method of Example 1, to produce 6/3-ethoxyethinyl-pregnan-5a-ol- 3,20-dione. Dehydration of the above compound with thionyl chloride in pyridine afforded 6(3-ethoxyethinylprogesterone.

Example 14 To 20 cc. of acetic acid containing 1 g. of 65-ethinylprogesterone, obtained as described in Example 10, was added 2 cc. of concentrated hydrochloric acid. The reaction mixture was kept at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate. The extract was then washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuo. The residue was chromatographed on neutral alumina, the first fractions eluted gave, after recrystallization from ether. 600 mg. of 6a(l-chlorovinyl)-progesterone, M.P. 158-161 C.; [ad -+94 (dioxane) A 240 m log :1 4.16.

Example By following the procedure described in the previous example, but using fl-ethinyl-testosterone as starting material, there was obtained 6a-(l-chloro-vinyl)-testosterone.

Example 16 In accordance with the method described in Example 1, 5 g. of 3,20-bis-ethylenedioxy-5a,6a-oxido-pregnanl7a,2l-diol-2l-monoacetate were converted successively into 6l8-ethinyl-3,20-bis-ethylenedioxy-5a,l7a,2l-triol-2lmonoacetate; Gfi-ethinyl-pregnan-Sa,l7a,2l-triol-3,20-dione-21-rnonoacetate and ofi-ethinyl-d -pregnane-l7a,2ldiol-3,20-dione.

l g. of the above compound was acetylated at C-17 with acetic anhydride-acetic acid, in the presence of ptoluenesulfonic acid, in accordance with the method described in Example 9, thus producing 6fi-ethinyl-A -pregnene-17a,2l-diol-3,20-dione diacetate.

The latter compound was hydrogenated by following the procedure of Example 1, thus producing 6,3-vinyl- A -pregnene-l7a,2l-diol-3,20-dione diacetate. Treatment of the latter compound with concentrated hydrochloric acid in acetic acid, in accordance with the method of Example 14, gave 6a-(l-chloro-vinyl)-A -pregnene-17a, 2l-di0l-3,20dione diacetate.

The starting material, namely 3,20-bis-ethylenedioxy- 5a,6a-oxido-pregnan-17a,2l-diol-Zl-monoacetate, was obtained from Ad-pregnen-l'la,2l-diol-3,20-dione by ketalization at C-3 and C20, acetylation at C-21 and epoxidation of the resulting Sa,6a-oxido-A -pregnene-l7a, 21-diol'3,20-dione Zl-acetate.

Example 17 To a solution of l g. of sodium metal in 500 cc. of liquid ammonia was added 2 g. of 6fi-ethinyl-3,20-bisethylenedioxy-pregnan-Six-01, intermediate in Example 11, dissolved in cc. of tetrahydrofurane. The mixture was stirred for 2 hours, 5 g. of ammonium chloride was then added, the ammonia was allowed to evaporate and the residue was subjected to chromatographic purification on neutral alumina. Recrystallization of the solid fractions from acetone-hexane yielded 6B-vinyl-3,20-bis-ethylenedioxy-pregnan-5a-ol.

Hydrolysis and dehydration of the above compound in accordance with the procedure of Example ll, gave 6B- vinyl-progesterone.

Example 18 By following the procedure of Example 11, 5 g. of 51,611 oxido 20 ethylenedioxy pregnan 3B ol acetate, obtained from A -pregnen-3fl-ol-20-one acetate by ketalization at C-ZO followed by epoxidation, in accordance with the preparation method of Example 1, were converted successively into 6,8-ethinyllfl-ethylenedioxy-pregnane 35,51: diol; 6B ethinyl pregnane 35,5a-diol- 20-one and 6fi-vinyl-pregnane-3fl,5a-diol-20-one.

In accordance with the preparation method described in Example 1, the following compounds listed under I were converted into the corresponding 5a,6ot-OXid03,20 diethylenedioxy derivatives, which in turn, by following the procedure described in Example 11 gave the fifl-ethinyl-compounds listed under ll.

Example I I1 19-nor-progestcrone progesterone.

2O ga-finoro-llfl-hydroxy- GB-cthinyLQwfluOro-llfiprogesterone. hydroxy-prc esterone. 21 Qa-chloro-ll-ketofifl-etlilnyl-9a-c lore-llprogcsterone. hem-progesterone. Cortisone fifl-ethinyl-eortisonc. lfiq-methylcortisoue 6t-othlny1-l6a-mcthylcortisone. ll-koto-progcstcronc fifl ethlnyl-ll-kctoprogesterone.

Example 25 By following the hydrogenation method described in Example 1, 6,8-ethinyl-lda-methyl-cortisone was converted into 6fi-vinyl-16a-rnethyl-cortisone.

Example 26 wherein R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of hydrogen and methyl; Y is selected from the group consisting of hydrogen,

/0 )1 :0, x and OH OH A is selected from the group consisting of H H lower alkyl ICH=CHR2 OH OAcyl \OH OH OH in which R is selected from the group consisting of hydrogen and lower alkyl, and acyl is derived from a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms; E is selected from the group consisting of ---CH--CHR and *CECR wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy.

2. fifi-ethinyl-testosterone.

3. 66-vinyl-testosterone.

4. 65-ethinyl-l7a-methyl-testosterone.

5. 6 B-vinyl-17a-ethinyl-testosterone.

6. A compound of the following formula:

R at

sisting of hydrogen and methyl; Y is selected from the group consisting of hydrogen,

OH OH A is selected from the group consisting of H H lower alkyl CH=CHR2 CIICR and in which R is selected from the group consisting of hydrogen and lower alkyl, and acyl is derived from a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms.

7. A compound of the following formula:

A is selected from the group consisting of 0H OAcyl lower alkyl cH oHR and 0 II in which R is selected from the group consisting of hydrogen and lower alkyl, and acyl is derived from a hydrocarbon carboxylic acid containing 1 to 12 carbon atoms; E is selected from the group consisting of CH=CHR and CECR3 wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy; R is selected from the group consisting of fi-hydroxy, keto, and lower alkylenedioxy.

9. 6B ethinyl 17a methyl androstane 5a,l7;9- diol-3-0ne.

l0. 6fi,l7a diethinyl androstane 511,173 diol 3- one.

11. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and lower alkyl; R is methyl; Y is selected from the group consisting of hydrogen,

H and carbon earboxylic acid containing from I to 12 carbon atoms.

. 6B-ethinyl-progesterone.

. 6fi-vinvyl-progesterone.

. GB-ethoxyethinyl-progresterone.

. 6/3-ethinyl-17a-acetoxy-progesterone.

. 6 ;8-viny1-17a-acetoxy-progesterone.

. 6/i-ethinyl-9a-fluoro-1IB-hydroxy-progesterone.

. A compound of the following formula:

wherein R is lower alkyl; R is selected from the group consisting of hydrogen and methyl; R and R are each selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms and E is selected from the group consisting of -CH=CHR and -CECR3 wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy.

19. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and lower alkyl; R is methyl; Y is selected from the group consisting of hydrogen,

n n =0, and o H i: lg

' --R HQ wherein R is selected from the group consisting of hydrogen and lower alkyl; R is methyl; E is selected from the group consisting of -CH---CHR and -CECR3 wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy; R and R are each selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms; R is selected from the group consisting of B-hydroxy, keto and lower alkylenedioxy.

23. GB-ethinyl-pregnane-5u-ol-3,20-dione.

24. 6fi-ethinyl-3,ZO-bis-ethylenedioxy-pregnane-Su-ol.

25. 6fi-vinyl-pregnane-Sa-o1-3,20-dione.

26. A compound of the following formula:

(EH10 R wherein R is selected from the group consisting of hydrogen and lower alkyl; E is selected from the group consisting of CH=CHR and C;.CR wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy; Y is selected from the group consisting of keto, fl-hydroxy and e-hydroxy; X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine; R and R are each selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing from 1 to 12 carbon atoms and R is selected from the group consisting of hydrogen, tit-methyl and B-rnethyl.

27. ofi-ethinyl-lopqnethyl-cortisone.

28. 66-ethinyl-cortisone.

29. 6fl-vinyl-cortisone.

30. dfi-vinyl-l6fl-methyl-cortisone.

31. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and lower alkyl; Y is selected from the group consisting of keto, fi-hydroxy and a-hydroxy; X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine; R and R are each selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing from 1 to 12 carbon atoms; R is selected from the group consisting of hydrogen, a-methyl and fi-methyl.

32. A compound of the following formula:

CHgOR wherein R is selected from the group consisting of hydrogen and lower alkyl; E is selected from the group consisting of CH=CHR and -CECR3 wherein R is selected from the group consisting of hydrogen, lower alkyl and lower alkoxy; Y is selected from the group consisting of keto, fi-hy-droxy, ot-hydroxy and d-hydI'U'CBIbOn carboxylic acyloxy containing from 1 to 12 carbon atoms; X is selected from the group consisting of hydrogen, chlorine, bromine and fluorine; R and R are selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group containing from 1 to 12. carbon atoms; R is selected from the group consisting of hydrogen, u-methyl and fl-methyl.

33. A process for the production of 6 B-1ower alkinyl- A -3-keto steroids selected from the class consisting of the androstane series and the pregnane series which comprises reacting a compound selected from the group consisting of a 5a,6a-oxido-androstane and a 50:,6ut-0Xid0- pregnane having an alkylenedioxy substituent at C-3 with an alkinyl magnesium halide in an inert solvent, hydrolyzing the thus formed 3-alkylenedioxy-5m-hydroxy- Gfl-alkinyl-steroid with an acid to obtain the corresponding 3-keto-5a-hydroxy-Gfi-alkinyl-steroid and treating with a dehydrating agent to obtain the corresponding 6B-alkiny1- A -3-lteto-steroid.

References Cited in the file of this patent Burn et al.: Journal Chem. Soc," December 19-59, pages 3808-3811.

Ellis: Journal Chem. Soc," June 1960, pages 2596- 2602. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 